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DNA Damage Repair Deficiency in Pancreatic Ductal Adenocarcinoma: Preclinical Models and Clinical Perspectives

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers worldwide, and survival rates have barely improved in decades. In the era of precision medicine, treatment strategies tailored to disease mutations have revolutionized cancer therapy. Next generation sequencing has found that up to a third of all PDAC tumors contain deleterious mutations in DNA damage repair (DDR) genes, highlighting the importance of these genes in PDAC. The mechanisms by which DDR gene mutations promote tumorigenesis, therapeutic response, and subsequent resistance are still not fully understood. Therefore, an opportunity exists to elucidate these processes and to uncover relevant therapeutic drug combinations and strategies to target DDR deficiency in PDAC. However, a constraint to preclinical research is due to limitations in appropriate laboratory experimental models. Models that effectively recapitulate their original cancer tend to provide high levels of predictivity and effective translation of preclinical findings to the clinic. In this review, we outline the occurrence and role of DDR deficiency in PDAC and provide an overview of clinical trials that target these pathways and the preclinical models such as 2D cell lines, 3D organoids and mouse models [genetically engineered mouse model (GEMM), and patient-derived xenograft (PDX)] used in PDAC DDR deficiency research.

SUBMITTER: Stoof J

PROVIDER: S-EPMC8546202 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Purpose: Compare pancreatic ductal adenocarcinoma (PDAC), preclinical models, by their transcriptome and drug response landscapes to evaluate their complementarity. Experimental Design: Three paired PDAC preclinical models-patient-derived xenografts (PDX), xenograft-derived pancreatic organoids (XDPO) and xenograft-derived primary cell cultures (XDPCC)-were derived from 20 patients and analyzed at the transcriptomic and chemosensitivity level. Transcriptomic characterization was performed using the basal-like/classical subtyping and the PDAC molecular gradient (PAMG). Chemosensitivity for gemcitabine, irinotecan, 5-fluorouracil and oxaliplatin was established and the associated biological pathways were determined using independent component analysis (ICA) on the transcriptome of each model. The selection criteria used to identify the different components was the chemosensitivity score (CSS) found for each drug in each model. Results: PDX was the most dispersed model whereas XDPO and XDPCC were mainly classical and basal-like, respectively. Chemosensitivity scoring determines that PDX and XDPO display a positive correlation for three out of four drugs tested, whereas PDX and XDPCC did not correlate. No match was observed for each tumor chemosensitivity in the different models. Finally, pathway analysis shows a significant association between PDX and XDPO for the chemosensitivity-associated pathways and PDX and XDPCC for the chemoresistance-associated pathways. Conclusions: Each PDAC preclinical model possesses a unique basal-like/classical transcriptomic phenotype that strongly influences their global chemosensitivity. Each preclinical model is imperfect but complementary, suggesting that a more representative approach of the clinical reality could be obtained by combining them. Translational Relevance: The identification of molecular signatures that underpin drug sensitivity to chemotherapy in PDAC remains clinically challenging. Importantly, the vast majority of studies using preclinical in vivo and in vitro models fail when transferred to patients in a clinical setting despite initially promising results. This study presents for the first time a comparison between three preclinical models directly derived from the same patients. We show that their applicability to preclinical studies should be considered with a complementary focus, avoiding tumor-based direct extrapolations, which might generate misleading conclusions and consequently the overlook of clinically relevant features.

Project description:Opinion statementMetastatic (and locally advanced) pancreatic adenocarcinoma (mPDA) represents a major challenge for the oncology community given the rising mortality burden from the disease and the preponderance of patients diagnosed with unresectable disease. Although systemic therapies have become more potent with the development of fluorouracil, irinotecan, and oxaliplatin (FOLFIRINOX) and gemcitabine plus nab-paclitaxel as first-line treatments, the median overall survival for patients treated with either of these regimens remains just above 1 year. A significant need exists to build upon the effectiveness of first-line regimens, incorporate tolerable maintenance treatments, and add effective later-line options for patients with this disease. We believe every newly diagnosed mPDA patient should undergo next-generation sequencing (NGS) testing, preferably from tumor tissue, to assess for the presence of DNA damage repair (DDR) defects, microsatellite instability, and other possible actionable molecular alterations (such as neurotrophic tropomysin receptor kinase (NTRK) fusions, anaplastic lymphoma kinase (ALK) rearrangements, or human epidermal growth factor receptor 2 (HER2) amplification). Existing clinical data suggests that patients, whose tumors harbor DDR defects, benefit from treatment with platinum-based chemotherapy and poly (ADP-ribose) polymerase (PARP) inhibitors. Preclinically, inhibitors of other critical players in DDR such as ataxia-telangiectasia and Rad3 related (ATR), ataxia-telangiectasia mutated (ATM), DNA-dependent protein kinase (DNA-PK), and WEE1 have demonstrated promising anti-tumor activity in PDA cell lines and xenografts. How to move forward the preclinical promise of these newer DDR-targeting therapies into rational clinical trial combinations and sequence PARP inhibitors in relation to platinum chemotherapy remain areas of tremendous clinical research interest. We believe clinical trials should be considered early for mPDA patients, in all treatment lines, so that novel therapies may be added to the treatment armamentarium for patients with this disease. Beyond NGS testing from tumor tissue, we believe it is important to consider germline genetic testing for all patients diagnosed with PDA given recent data suggesting a much stronger hereditary component of the disease than previously understood, and the potential screening implications for family members.

Project description:Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer with high incidences of p53 mutations. AZD1775 (adavosertib, previously MK-1775) is a small molecule WEE1 inhibitor that abrogates the G2M checkpoint and can potentially synergize with DNA damaging therapies commonly used in PDAC treatment. The purpose of this study was to identify combination partners for AZD1775, including standard chemotherapy or targeted agents, in PDAC preclinical models. Low powered preliminary screens demonstrated that two of the four PDX models responded better to the combinations of AZD1775 with irinotecan or capecitabine than to either single agent. Following the screens, two full powered PDAC PDX models of differing p53 status were tested with the combinations of AZD1775 and irinotecan or capecitabine. The combinations of AZD1775 and SN38 or 5-FU were also tested on PDAC cell lines. Cellular proliferation was measured using an IncuCyte Live Cell Imager and apoptosis was measured using a Caspase-Glo 3/7 assay. Flow cytometry was conducted to measure alterations in cell cycle distribution. Western blot analysis was used to determine the effects of the drug combinations on downstream effectors. In PDX models with mutated p53 status, there was significant tumor growth inhibition from the combination of AZD1775 with irinotecan or capecitabine (P ≤ 0.03), while PDX models with wild type p53 did not show anti-tumor synergy from the same combinations (P ≥ 0.08). The combination of AZD1775 with SN38 or 5-FU significantly decreased proliferation in all PDAC cell lines, and enhanced apoptosis in multiple cell lines. Cell cycle distribution was disrupted from the combination of AZD1775 with SN38 or 5-FU which was recorded as G2M arrest and decreased G1 phase. AZD1775 inhibited phospho-CDC2 and increased the expression of γH2AX that was either maintained or enhanced after combination with SN38 or 5-FU. The combination of AZD1775 with irinotecan/SN38 or capecitabine/5-FU showed anti-tumor effects in vivo and in vitro in PDAC models. These results support further investigation for these combination strategies to enhance outcomes for PDAC patients.

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DNA Damage Repair Deficiency in Pancreatic Ductal Adenocarcinoma: Preclinical Models and Clinical Perspectives

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